The long-term goal of this proposal is to develop more effective therapies for cancer, specifically pancreatic cancer. The specific focus of this proposal is to improve upon the anti-cancer activity of the drug gemcytabine. This will be accomplished by synthesizing novel conjugates of gemcytabine in a form that enables increased pathways for uptake into cancer cells and additional paths to rapid activation once inside cells. Gemcytabine requires activation within a cell before it can demonstrate its anti-cancer activity. The novel compounds will incorporate a form of gemcytabine already preactivated. The specific aims of this project are: (1) To synthesize 5 novel gemcytabine based compounds and assess their stability in plasma and laboratory conditions; and (2), complete characterization of these novel compound's activities in a number of cancer cell lines. This will include quantitation of the compounds effects on cell killing, colony formation ability and cell migration ability. In addition we will quantitate the rate of formation of the most active forms of gemcytabine found within the cells at various times after exposure to the drug and novel compounds. To investigate the mechanism of cellular uptake, activity and bioanalytical endpoints will be assessed in the presence and absence of inhibitors of the standard nucleoside transporters used by Gem. Positive results from this proposed research will provide multiple assets to MBC Pharma's commercialization efforts. A new lead compound for treating pancreatic cancer will provide assets for licensing. In addition, the demonstration of a lead compound from novel drug platform will enable the potential development of multiple compounds for different indications. It is anticipated that this technology will ultimately result in therapeutic agents that will significanty improve the outcomes of cancer patients.